1. Field of the Invention
The present inventive subject matter relates to amorphous drug beads comprising an amorphous active drug and an organic surfactant having improved solubility, absorption and wettability characteristics. The present inventive subject matter further relates to methods of preparing the amorphous drug beads, wherein molten drug beads are subject to a cooling step with or without shear.
2. Description of the Related Art
Over the years, compositions and methods have been developed to achieve improved delivery of a therapeutically effective amount of a drug. In particular, compositions and methods providing enhanced solubility, absorption and wettability characteristics of a drug, resulting in a desired dissolution rate in vivo, have been sought.
Among the reasons for the increased focus in this field of art are the poor solubility characteristics of new pharmaceuticals. Many newly developed active drugs possess poor absorption profiles and unfavorable dissolution characteristics. A cursory review of pharmacokinetic characteristics of several recently developed active drugs suggests that more than 40% of these drug substances have an aqueous solubility below 1 mg/ml, while 32% have an aqueous solubility below 0.1 mg/ml. The low solubility of these active drugs in water and in organic solvents translates into a lowered ability to deliver the drug to an animal in need thereof.
For example, potential absorption problems may occur via the oral route of administration unless the active substance has an aqueous solubility above 10 mg/ml over a pH range of 1–7. Pharmacological testing is also hampered since, following oral or intramuscular administration, it is not possible to test the bioavailability of an active drug due to its low solubility. Accordingly, the implementation of absorption enhancing methods is currently a major field of research in formulating and developing drug dosage forms.
One known method for overcoming the problems of a low dissolution rate of an active drug is to reduce the particle size of the drug, thereby causing the surface area available for interaction with the fluids to be significantly increased. For drugs where absorption is limited by dissolution rate, particle size reduction clearly represents a viable means for increasing bioavailability. In particular, the dissolution rate of a drug increases as the particle surface area increases in accordance with the Noyes-Whitney law. This causes an increase in the rate of flooding of active compounds, and the maximum plasma level is reached faster (e.g. oral or i.v. administration of micro- and nano-particulate drug crystals). Aqueous solubility of active drug substances is also improved by particle size reduction.
One advantage to thusly reducing the particle size of active drugs is that intravenous administration of insoluble or sparingly soluble active drugs can be accomplished. Moreover, sparingly soluble active drugs can be injected without blockade by blood capillaries.
Another advantage is a reduction in the injection volume of active drugs. For example, if water-solubility is low, a relatively large volume is administered. Alternatively, if micro- and nano-particulate drug crystals of a reduced size are used, they can be dispersed to form a saturated solution of the active compound, thereby reducing the volume of the injection.
Small particle drugs can also more readily be employed for controlled drug delivery. For example, after oral administration, oral immunization could take place via the M cells in the gastrointestinal tract, and selective concentration in the absorption windows of the gastrointestinal tract could be achieved via bioadhesives.
Another use for small particle active drugs is drug targeting. After intravenous injection, it is well known in the art that particles accumulate specifically in certain organs, e.g. liver, spleen, or bone marrow, as a function of their surface properties. Therefore, after administration, particle accumulation in targeted organs can be achieved. Targeted accumulation of the active compound at the site of action reduces side effects and increases therapeutic efficiency.
Accordingly, many techniques have been developed to reduce the particle size of an active drug to take advantage of these beneficial properties. The majority of these techniques relate to various milling techniques wherein the active drug is comminuted by dry grinding techniques and subsequent fractionation. However, these milling techniques have a significant disadvantage of loss of the active compound during the milling process. Sometimes the milling process may waste more than 90% of the active compound, thereby greatly reducing cost effectiveness.
One known milling technique attempts to circumvent this loss by providing for a high molecular weight polymer which provides a higher processing temperature and a longer period for the manipulation of a resin and drug in a mill or other processing machine. These conditions increase the amount of active drug that can be dissolved in the resin without degrading the resin, and the relative rigidity of the resin can assist in the grinding to form granular particles or powders of the active drug.
In this regard, U.S. Pat. No. 5,246,707, the contents of which are herein incorporated by reference in their entirety, describes surfactant-stabilized micro-particles, which may additionally comprise iron particles within the micro-particles, in order to allow location of the particles via magnetic fields.
Further, U.S. Pat. No. 4,540,602, the contents of which are herein incorporated be reference in their entirety, describes a process for the preparation of micro- and nano-particulate drug crystals by wet grinding. U.S. Pat. No. 5,145,684, the contents of which are herein incorporated by reference in their entirety, additionally describes wet grinding of active drugs with a pearl mill. A further reduction in the particle size provided by such mills is possible if the viscosity of the dispersion medium is increased while the speed of rotation remains constant.
However, the above outlined milling techniques have the disadvantages of not being amenable to industries of scale and result in relatively large particles. Moreover, the techniques are only applicable to certain classes of molecules and do not ensure homogenous results.
One technique to overcome these disadvantages is to produce the active drug suspensions by precipitation. European Patent Application No. 0 275 796 A1, the contents of which are herein incorporated by reference in their entirety, discloses the preparation of a liquid phase consisting of a solution of an active drug added to a second liquid phase consisting of a non-solvent or a mixture of non-solvents of the active drug to which one or more surfactants may be added, wherein both phases are mixed with moderate agitation to produce a colloidal suspension of particles of the active drug. The non-solvent or the mixture of non-solvents for the active drug is miscible in all proportions with the solvent or mixture of solvents for the active drug.
However, the disadvantage of this technique is that its effectiveness is limited to substances sufficiently soluble in water or a given solvent.
Accordingly, there remains a need for a composition and method which achieves improved delivery of a therapeutically effective amount of an active drug without providing any of the disadvantages noted above.
U.S. Pat. No. 5,858,410, the contents of which are herein incorporated by reference in their entirety, attempts to sidestep the problem of insoluble or sparingly soluble drugs by avoiding a precipitation technique. In particular, this patent discloses that active drugs with a low solubility can have an increased dissolution rate by using an ultrasonic probe, a ball mill, or a pearl mill, wherein the drug is comminuted by using cavitation or shearing and impact forces, with introduction of a high amount of energy, without prior conversion into a melt.
However, a disadvantage of this milling technique is that the residual content of solvents in the product can only be removed with great difficulty, delaying crystallization and often producing a high proportion of large particles.
Moreover, recent investigations directly contravene the teachings of this patent by suggesting that crystals derived from a melt give rise to significant advantages over crystals derived from milling. In particular, crystals co-precipitated out of a melt are significantly less irritating than the solid dispersions created by milling (Khan, Shojael, Karnachi and Keddy, “Comparative Evaluation of Controlled-Release Solid Oral Dosage Forms Prepared with Solid Dispersions and Co-precipitates”, Pharmaceutical Technology, May 1999). These recent investigations further provide in vivo ulcerogenicity data clearly indicating that drugs co-precipitated from a melt produce less gastric irritation than drug dispersions created by milling.
However, no known methods provide an acceptable active dosage form produced from a melt comprising an amorphous active drug and an organic surfactant wherein the organic surfactant coats the amorphous active drug.
Accordingly, there is a need for amorphous active drug products having improved solubility, absorption, and wettability characteristics, and for processes to manufacture such drug products easily and reliably.